Human Genetic Evidence that Common Variants near PIK3CG are Associated with Atherosclerotic Plaque Hemorrhage and Vessel Density

Aim: Atherosclerotic plaque characteristics may vary among individuals, in part due to heritable factors. The genetic architecture of plaque phenotypes is largely unknown. A common variant (rs17398575-A) near PIK3CG on chromosome 7 has previously been associated with carotid plaque presence. Animal models suggest that PIK3CG may play a role in plaque formation through neovascularization. We hypothesized that the PIK3CG variant is associated with intraplaque hemorrhage and vessel density in human plaque tissue. Methods: We collected 831 patients in the Athero-Express Biobank Study, all of whom underwent carotid endarterectomy and genotyped them using Affymetrix SNP 5.0. We tested PIK3CG variants for association to intraplaque hemorrhage and vessel density using logistic and linear regression model, respectively, correcting for age, gender and principal components. We used the BiKE cohort to assess the effect of PIK3CG variants on PIK3CG expression in circulating monocytes (N=95) and in carotid plaques (N=126). Results: The reported PIK3CG variant, rs17398575 (risk allele A, frequency = 0.72), was nominally significantly associated with intraplaque hemorrhage (OR=1.40 [1.10-1.69 95% CI], p=0.0271) and vessel density (β=0.095 [0.0415 s.e.m.], p=0.0221). We also report another nearby variant, rs849429 (risk allele A, frequency=0.49), but uncorrelated to rs17398575, associated with intraplaque vessel density (β=-0.164 [0.0361 s.e.m.], p=6.70×10-6). The SNP dependent PIK3CG mRNA expression demonstrated a differential effect in the vascular wall (p=0.783 for rs17398575; p=0.0198 for rs849429) compared to circulating monocytes (p=0.0261 for rs17398575; p=0.350 for rs849429). Conclusion: To our knowledge this is the first report involving the association of common genetic variants to histological plaque phenotypes. These results require further replication in independent cohorts. Further research should focus on elucidating the underlying mechanisms leading to plaque vessel formation and intraplaque hemorrhage, as both have been demonstrated to associate with secondary cardiovascular disease.